1. Field of the Invention
This invention relates to a method of preparing 5 to 7 membered cyclic ethers or thioethers by cyclization of unsaturated alcohols, thiols or thioesters with phenyl selenenyl halide. In a preferred embodiment, the invention also relates to a method of making oxygen and sulfur analogs of prostacyclin using the aforementioned synthetic methodology.
2. Description of the Prior Art
The importance of oxygen and sulfur heterocyclic compounds in the field of natural products has led to a demand for efficient synthetic methods to prepare these types of derivatives. Sulfur heterocycles are of importance in, for example, the .beta.-lactam antibiotic field (Sammes, P., Chem. Revs. 76, 113 (1976)). Oxygen heterocyclic compounds, their sulfur analogs and derivatives thereof are important in the rapidly expanding field of prostacyclin research. Prostacyclin (I) is a recently discovered member of ##STR3## the family of prostaglandins (Vane, C. and En. News, Dec. 20, 1976). Its technical name is 6,9.alpha.-oxido-11.alpha.,15.alpha.-dihydroxyprosta-(Z)5, (E)13-dienoic acid. It is a cis-fused, bicyclic system which contains an acid-labile enol ether system. Prostacyclin has been involved in the regulation of blood platelet aggregation and the constriction and dilation of arteries. It is biosynthetically derived from its precursor, endoperoxide, which in turn is derived from the available pool of fatty acid precursors. The endoperoxide precursor also generates, via another enzymatic system, a compound named thromboxane A.sub.2, which shows opposite effects to prostacyclin. Both prostacyclins and thromboxanes exist in a delicate equilibrium and help to maintain the body balance of blood platelet aggregation versus dissolution, and arterial constriction versus dilation. Both compounds are hydrolyzed to prostaglandins.
The use of prostacyclins has been suggested in the treatment of blood clotting in diseased vessels of patients with cardiovascular problems. Since prostacyclin has retroactive action and not only inhibits blood clotting but also dissolves already formed clots, it can be used in heart attack cases and artherosclerosis. Increased susceptibility of platelets to aggregation accompanies vascular complications in diabetes, in cerebral strokes associated with essential hypertension and in post heart infarct cases. These are other areas where prostacyclin activity can be highly beneficial. The main drawback of the use of prostacyclin for these applications is its very short biological half-life of 2 minutes. This prevents the externally provided drug from reaching its target tissues intact. The need to maintain the drug in a totally anhydrous condition also prevents its ready shipment, storage and testing for pharmacological applications. If an analog or derivative of prostacyclin can be formed which is stable and shows similar effects on blood platelets and arteries, it would have wide applications in pharmacology and the treatment of cardiovascular and related diseases.
There has emerged, with the discovery of prostacyclin, the need to prepare stable, pharmaceutically active isomers and analogs or derivatives thereof which can be used clinically. Sulfur analogs of prostacyclin are particularly promising in this respect. There has also emerged, as a consequence, the need to develop a general, mild, fast and synthetically useful method to prepare cyclic ethers, thioethers and their derivatives. Particularly useful for the prostacyclin field would be a method which could induce cyclization between the oxygen atom at position C-9 and carbon 6 of the readily obtained PGF.sub.2.alpha. prostaglandin derivative of formula II (Given here with its standard numbering system): ##STR4## If in this formula, one replaced the hydroxy group at position 9 with a thiol or a thioester, and used the same cyclization methodology, one would have a general method of preparing prostacyclin-type derivatives and analogs. The problem thus consists of devising a mild method to cyclize unsaturated alcohols, thiols or thioesters.
It is known (Delmon, E., et al, Helvetica Chim. Acta., 54, 546 (1971)) to cyclize unsaturated alcohols with halogens to yield cyclic ethers. However, the reaction requires aqueous basic media which is incompatible with solubility properties and other functionalities present in the molecules being treated. In addition, the incompatibility of a rather large number of important functionalities and protecting groups with halogens decreases the area of applicability of this conventional procedure. It is also known to cyclize unsaturated alcohols and thiols using an acid or metal as a catalyst. (Brown, et al, Organometal. Chem. Synth., 1, 7 (1970)). The many acidlabile protecting groups or functionalities used in organic synthesis, limit this method to carefully selected cases where acid induced side reactions constitute no problem. The use of phenyl selenium reagents has recently been shown to be successful in the construction of open-chain allylic acetates and ethers from olefins (Sharpless, K. B., et al, J. Org. Chem., 39, 429 (1974)); of enones from ketones (Reich, H. J., et al, J. Amer. Chem. Soc., 97, 5434 (1975)). These precedents have led the inventors to investigate and develop the use of phenyl selenium reagents in the construction of cyclic ethers, thiols and their derivatives. Of particular interest is the use of these reagents in the construction of prostacyclin derivatives and analogs.